This application represents the competitive renewal of a Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer originating from the Gastrointestinal (GI) Malignancies Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). The main goal of the DF/HCC SPORE in GI Cancer is the translation of biological and technological advances into improvements in prevention, diagnostics, predictors of outcome, and advances in the treatment of gastrointestinal malignancies. The DF/HCC SPORE in GI Cancer includes researchers from all Harvard-affiliated hospitals and institutions: the Dana-Farber Cancer Institute, the Brigham and Women's Hospital, the Massachusetts General Hospital, the Beth Israel Deaconess Medical Center, Children's Hospital of Boston, Harvard Medical School, Harvard School of Public Health, and Broad Institute. Five major projects are proposed including: 1) Molecular imaging for detection of high grade dysplasia in Barrett's Esophagus; 2) Defining the role of vitamin D in colorectal carcinogenesis and cancer survival; 3) Identifying novel therapeutic strategies for KRAS-mutant colorectal cancer; 4) Overcoming resistance to RAF inhibition in BRAF-mutant colorectal cancer; and 5) Overcoming Resistance to KIT/PDGFRA Inhibition in GIST. These projects will be integrated by three cores: 1) Administration, Evaluation & Planning; 2) Tissue & Pathology; and 3) Biostatistics & Bioinformatics. The SPORE application outlines a Developmental Projects Program that includes a plan of selection of new projects and documents 18 highly innovative and productive developmental projects that have been supported during the current funding cycle. We also include a Career Development Program that outlines a mechanism for the identification and support of talented young investigators in GI cancer and report on our success in supporting and mentoring 15 young investigators during the current funding cycle. The projects and cores proposed in this application are highly integrated with present DF/HCC core resources, and involve key collaborations with investigators from other existing SPOREs and cancer centers. The renewal of this GI SPORE at DF/HCC will combine leading Harvard researchers in basic, translational, and clinical sciences into a program that has the focus and coordination required to produce meaningful advances in the diagnosis, treatment, and prevention of GI cancers.